The objective for this research project is the synthesis and preliminary evaluation of derivatives of opioid ligands derived from agents which interact with opioid receptor subtypes. It is anticipated that preparation and testing of these compounds will provide greater understanding of the structural requirements at opioid receptors, and may lead to further characterization of opioid receptor subtypes. Ligands which interact at Mu, Delta, Kappa, Sigma opioid receptor subtypes will be converted into compounds with covalent binding potential. Based on previous work with Alpha-methylene-Gamma-lactones, derived from naltrexone, this moiety will be incorporated. Additional potentially selective ligands which incorporate epoxide, glycidate ester, thiirane and isothiocyanate groups are proposed. Methods of incorporation of tritium into Alpha-methylene-Gamma-lactones are proposed. The compounds will be tested for analgesia and antagonism activity through the CPDD. In vitro work in opioid receptor preparations and smooth muscle (rat vas deferens and guinea pig ileum) will be arranged through the CPDD and with collaborators.